Molecular signatures of N-nitroso compounds in Caco-2 cells: implications for colon carcinogenesis

D.G. Hebels*, D.G. Jennen, J.C. Kleinjans, T.M. de Kok

*Corresponding author for this work

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    N-nitroso compounds (NOC) are genotoxic, carcinogenic to animals, and may play a role in human cancer development. Since the gastro-intestinal tract is an important route of exposure through endogenous nitrosation, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate these genomic responses, we analysed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1muM) and N-methyl-N-nitrosurea (MNU, 1mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100mM), N-nitrosopiperidine (NPIP, 40mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 hours of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and pro-inflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon.
    Original languageEnglish
    Pages (from-to)290-300
    JournalToxicological Sciences
    Issue number2
    Publication statusPublished - 1 Jan 2009

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